Co-resistance necessitating use of less effective or relatively toxic reserve antibiotics (aminoglycosides, tigecycline and colistin/polymyxin B) may worsen survival. We investigated difficult-to-treat resistance (DTR) in gram-negative bloodstream infections (GNBSIs) defined by absence of susceptibility to all first-line agents (carbapenems, beta-lactams and fluoroquinolones (FQ) using a large clinical database of US hospitals. We found that survival in antimicrobial-resistant GNBSI is highly contingent on presence of active first-line option(s); DTR limits treatment options to reserve agents, including aminoglycosides, which are far from universally active. DTR remained infrequent (1%) among GNBSI, but occurred at half of the hospitals examined and across all US regions. This work has been presented at the Annual Meetings of the Infectious Diseases Society of America, in New Orleans, LA in October 2016 and Society of Critical Care Medicine, in San Antonio, TX in February 2018. A manuscript on this work has been published in Clinical Infectious Diseases. We went on to validate our findings using the Cerner Health facts repository of electronic health records and the associated manuscript is now published in Open Forum Infectious Diseases. We also went on to study the landscape of emerging antibiotics to understand their real-world use and demand which has generated two manuscript that are currently under peer review. As part of ongoing work, we are performing national extrapolations to understand recent trends in difficult-to-treat resistance, conducting an analysis of burden and impact of inappropriate antibiotic therapy in bacteremia and sepsis and are also attempting to determine whether shorter courses of therapy are sufficient in clinically suspected serious infection when no pathogens are identified, as a move to promote stewardship.